Propofol (2,6-diisopropylphenol or 2,6-bis(1-methylethyl)-phenol)) is an anesthetic agent for use in the induction and maintenance of anesthesia or sedation. Propofol is formulated in an oil-in-water emulsion for intravenous injection due to its poor water solubility. For example, Diprivan® is an oil-in-water emulsion comprising propofol, soybean oil, and egg lecithin approved by the FDA in 1989. These emulsion products have many undesirable attributes. Many patients complain of moderate to severe pain upon injection. The fatty components of the emulsion, such as egg lecithin, pose an allergic risk to some patients. Emulsions are difficult to sterilize by autoclave or filtration, so these products are not considered to be antimicrobially preserved under USP standards. As such, strict aseptic techniques must be maintained during handling to decrease the risk of microbial contamination, and consequent infection in patients. These issues and additional manufacturing difficulties have resulted in several recalls of propofol emulsions and a long-term drug shortage.
Modifications to the emulsion formulations comprising propofol have been made. For instance, antimicrobial agents such as benzyl alcohol and sodium benzoate are included in emulsion products to reduce microbial contamination, e.g., U.S. Pat. Nos. 6,140,374 and 6,147,122. However, these antimicrobial agents can cause toxicity, especially at high concentration. Also, attempts have been made to reduce injection site pain by raising the pH of the emulsion to above pH 6.5, e.g., U.S. Pat. No. 8,546,453.
Efforts have been made to develop non-emulsion propofol products in view of the undesirable attributes associated with the emulsion products and supply shortage. For example, U.S. Pat. No. 7,034,013 relates to a non-emulsion propofol product comprising propofol, cyclodextrin such as sulfobutyl ether β-cyclodextrin, and water, as well as other excipients. It was also known that the amount of sulfobutyl ether β-cyclodextrin is preferably in the range of 18-20% or more for a 10 mg/mL propofol solution so the drug remains in solution during manufacturing and storage. The excess amount of sulfobutyl ether β-cyclodextrin was believed to reduce injection site pain. However, despite such efforts, development of non-emulsion propofol products has not been successful. Diprivan® and its generic counterparts remain the only FDA-approved propofol products today.